The present invention discloses a novel process for the synthesis of the macrolide antibiotic 9-deoxo-11-deoxy-9,11 -{imino [2- (2-methoxyethoxy)ethylidene]oxy}-(9S)-erythromycin, hereinafter referred to as dirithromycin.
Dirithromycin is a derivative of and has a similar spectrum of activity to erythromycin. However, pharmacokinetic studies of dirithromycin summarized in Drugs of the Future, 14:112 (1989), reveal the antibiotic to have lower peak but longer-lasting serum levels than erythromycin in all species studied. Dirithromycin also has the advantageous property of rapid distribution of high concentrations of antibiotic activity to all tissues. These characteristics would be expected to make possible higher doses in the target organs.
Applicants have discovered that dirithromycin may be produced in an alternate manner to the aldehyde/erythromycylamine condensation reaction disclosed in previous reports. For example, Maier et al., in U.S. Pat. No. 4,048,306, which is herein incorporated by reference, reports that polar organic solvents are the preferred solvents for this reaction. More specifically, aqueous dioxane was used as the solvent for condensation of 2-(2-methoxyethoxy)acetaldehyde diethyl acetal and erythromycylamine in the presence of an acidic ion-exchange resin. Maier et al. states that an aldehyde is formed from hydrolysis of the acetal which presumably reacts in turn erythromycylamine to form the dirithromycin final product. Under the reaction conditions proposed by Maier et al., the dirithromycin product is soluble in the reaction mixture and therefore, must be isolated by evaporation of the solvent followed by chromatographic purification of the residue and recrystallization from ether/petroleum ether.